Preparation of 3-fluorosalicylaldehyde



Patented Nov. 29, 1951 PREPARATION OF 3-FLUOROSALICYL- ALDEHYDE Edgar C. Britton and James D. Head, Midland,

Mich., assignors to The Dow Chemical Company, Midland, Mich., a corporation of Delaware No Drawing. Original application December 23,

1949, Serial No. 134,836. Divided and this application January 19, 1951, Serial No. 206,926

1 Claim.

This invention relates to an improved method for the production of 3-fluorosalicylaldehyde.

The importance of B-fiuorosalicylaldehyde has been greatly increased as a consequence of recent chemical research. Tsumaki (see J. Chem. Soc Japan, 58, 1288 (1937)) showed that the cobalt chelate of the Schiiis base from salicylaldehyde and ethylene diamine would absorb oxygen, and that the absorption was reversible Calvin (see J. Am. Chem. Soc, 68, 2254 (1945)) investigated various compounds similar in structure to salicylaldehyde, hi goal being to determine what material formed a cobalt chelate best suited for commercial use (e. g., for absorbing oxygen from air and thereby providing an inexpensive means for separating oxygen from nitrogen of the air). The most efficient cobalt chelate found by Calvin was that from 3-fiuorosalicylaldehyde. The present invention is based on the discovery of a commercially practical method for producing.

3-fiuorosalicylaldehyde.

According to the invention 3-fluorosalicylaldehyde is produced by a new method involving the steps of: (l) diazotizing 5-chloro-o-anisidine and converting the resulting diazotized material to 4-chloro-2-fluoroanisole by (A) forming the diazonium fluoborate by the action of fluoboric acid, and (B) thermally decomposing the diazonium fluoborate; (2) hydrolyzing the methoxy radical of the 4-ch1oro-2-fluoroanisole to produce 4-chloro-2-fiuorophenol; (3) converting the 4-chloro-2-fluorophenol to 4-chloro-6-fiuor-alpha-dimethyl-amino-o-cresol by the action thereon of dimethyl amine and formaldehyde; (4) convertin the 4-chloro-G-fluoro-alpha-dimethylamino-o-cresol to 5-chloro-3-fluoro-saligenin diacetate by the action of acetic acid; and (5) producing 3-fiuorosalicylaldehyde from the 5chloro-3-fiuorosaligenin diacetate. Although the present method of producing 3-fluorosalicylaldehyde from a simple derivative of aniline is believed to be novel, the critical aspect of the process of the invention resides in the introduction of a chloro substituent into the benzene ring of o-anisidine to block one of the reactive positions and thereby prevent undesired side reactions in later processing. An intermediateproduct is subsequently dechlorinated to produce the desired structure.

The production of 3-fluorosalicylaldehyde even according to the advantageous method of 4-chloro-2-fluorophenol molecule.

the invention is a lengthy operation. Furthermore, practicing the method requires the production of several compounds not known to the art at the time of our invention, and the process of the invention is practical only because of the specific structure of the various intermediates produced, and because the various reactions involved are conducted in a specific order. The essential structural characteristic of the intermediates produced in the practice of the invention is the chloro group in the position meta to that occupied by the fluoro substituent. It is essential that this chloro substituent be present in the molecule, and that it be introduced prior to the introduction of the fluoro group. The presence of this chlorine is required when formaldehyde and dimethylamine are used to introduce the group -CH2N(CH3)2 into the If this reaction were conducted with Z-fiuorophenol (instead of with 4-chloro-2-fluorophenol) two isomers would be formed, i. e.,

OH H and These two isomers would be extremely difficult to separate because of their closely similar characteristics. By the method of theinvention, the chloro group blocks the position para to the hydroxyl group and thereby assures that only the desired substitution (ortho to the hydroxyl group) occurs.

The production of 3-fiuorosalicylaldehyde according to the invention is illustrated by the. following simplified chemical diagrams. Two ays of converting the intermediate 5-Ch1010-3-fill0e rosaligenin diacetate to 3-fiuoro-salicylaldehyde, in the final sta es of thenrocess. are shown 605 7 T 7 T e 26 0H e 066 m 0E6 J6 e 05 Q 05' mo 7 i i am gos omo o 7 m 26cm 7 V @005 mo zo woe;

em m Eo w o o "0 \v @0525 Q0 M660 6 V 6 6 6 6 6 6 mzx o mv V 7 Em A T I II T I V. m mo o wo m w m #62226 omom m in e :22 62 522 E2 0 05 V v i O mo mo H60 6o "moo moo o ooi 7 W 0 05 o The preferred way of producing the 5-ch1dro-oiron and water; the -chloro-z-nitroanisole is anisidine hydrochloride starting material of the converted to the hydrochloride by the action of process is by nitrating 'l,-==-diehlorbenzene end 79 H01 in the presence of acetic acid methylating the 2,5-di.ch1oronitrobenzene pro- In the final stages of the procedure illustrated duced, using methyl alcohol and sodium hy- V by the foregoing simplified diagrams the interdroxide for the methylation, and then reducing 7 mediate 5-chloro-3-fii1orosa1igenin diacetate is theNOz groupof'the 4-ch1oro-2-nitroanisole to converted to 3-fluorosalicylaldehydeby either of produce 5-ch1oro-o-anisidine by the action of 7- two geiieral methods; each of the genera methods involves a dechlorlnatlon and a deesterification. The dechlorination and de-esteriflcation are carried out to produce either 3-v F- CHZA in which A is hydrogen or hydroxyl). The details of the method by which 3-fluorosalicylaldehyde is produced as a final step in the process of the invention are determined by whether the dechlorination and de-esterification are conducted to produce 3-fluorosaligenin or G-fluoroo-cresol. If the dechlorination and de-esteriflcation are conducted to produce G-fluoro-ocresol, 3-fluorosalicylaldehyde is prepared therefrom by the following steps: (1) conversion to di-(6-fluoro-o-tolyl-) carbonate; (2) production therefrom, by chlorination, of di-(fi-fluoroalpha,alpha-dichloro-o-tolyl-) carbonate; (3) hydrolysis of the chlorinated compound to 3- f luorosalicylaldehyde, as is claimed in our co pending application Serial No. 134,836, filed December 23, 1949, of which the present application is a division. If 3-fluorosaligenin (rather than G-fluoro-o-cresol) is produced by the dechlorination and de-esterification, 3-fluorosalicylaldehyde is produced therefrom by oxidation. The'first described method is preferred because of the comparatively high yield of 3-fluorosalicylaldehyde which results therefrom, and because the, compounds produced in carrying out the method are relatively stable so that less care is required to prevent undesirable side reactions. The second described method is preferred be-- cause the desired product can be produced thereby at a substantially lower chemical cost.

Example 3-fluorosalicylaldehyde was produced from 5- chloro-o-anisidine hydrochloride according to the following procedure:

5 chloro o anisidine hydrochloride (193 grams) was mixed with hydrochloric acid (320 grams of a 3''! weight per cent aqueous acid and 380 cc. of water), and the solution which resulted was cooled to a temperature between 5 C. and C. by adding pulverized solid carbon dioxide thereto. While this temperature was thus maintained by continued additions, a saturated aqueous solution of sodium nitrite (150 cc.) was added over a period of 45 minutes with vigorous stirring. The rate of sodium nitrite addition was the maximum that could be used without libertaion of N02. The mixture was then warmed to 20 C. to complete diazotization, and a mixture of boric acid (136 grams) and hydrofluoric acid (325 grams of a 60 weight per cent aqueous solution) was added thereto. The solution was then cooled to about -25 0., and the solids were separated by filtration. The collected precipitate was washed with ethylene dichloride (250 cc.) and vacuum dried about 16 hours at room temperature (total pressure 3 to 8 inches Hg). The dried precipitate was placed in a flask and thermally decomposed, under vacuum, by heating the entire surface of the flask to insure escape of the liquid decomposition products; heating was continued to dull redness. The decomposition products were collected in an absorption train, the absorbents being (1) a water-ice slurry, and (2) a sodium hydroxide solution; vacuum was applied to the flask containing the sodium hydroxide. The organic decomposition products were recovered by steam distillaiton from the combined iceand sodium hydroxide-absorbents. The organic layer in the distillate was separated and dried over calcium chloride (about 10 grams), and pure 4-chloro-2- fluoroanisole (86 grams) was isolated by a final distillation. The overall conversion of fi-chloroo-anisidine hydrochloride to 4-chloro-2- fluoroanisole was about 54 per cent.

A mixture of 4-chloro-2-fluoroanisole (255 grams) and dichlorofluorobenzene (345 grams) was combined with hydrobromic acid (1800 grams of a 50 weight per cent aqueous solution), and the resulting solution was refluxed with vigorous stirring, for 16 hours. A clear liquid product was separated from the mixture remaining (after the refluxing) by a steam distillation; this clear product was extracted with sodium hydroxide (1 liter of a 10 per cent by weight aqueous solution). The crude caustic solution of the desired product was separated from the dichloro-fluorobenzene introduced with the .4- chloro-2-fiuoroanisole, and was heated to distill non-phenolic material therefrom; it was then acidified with sulfuric acid (120 grams of a 20 weight per cent aqueous solution) and the i-chloro-z-fluorophenol (230 grams) was separated by steam distillation from the resulting acidic aqueous layer. This amounts to a 98.5 per cent yield of 4-ch1oro2-fluorophenol, based upon the anisole consumed.

The 4-chloro-2-fiuorophenol (1042 grams) and dimethylamine (2615 grams of a 25 weight per cent aqueous solution) were added to a flask, and the mixture was cooled to 30 C. Aqueous formaldehyde (a total of 625 grams of a 40 weight per cent solution) was added stepwise with stirring to this mixture. The formaldehyde was added at such a rate thatthe temperature of the mixture did not rise above 45 C. When 7 the formaldehyde-addition was complete, the

mixture was stirred thoroughly and was heated on a steam bath at about C. for 18 hours. The liquid in the flask was then cooled and the oily product which had separated was solidified by the addition of afew crystals of 4-chloro-alphadimethylamino-B-fluoro o cresol. The solid product (l-chloro alpha dimethylamino 6 fluoro-o-cresol) which formed was separated by filtration. The filtrate was then cooled, concentrated, and steam distilled to recover further 4-chloro-alpha-dimethylamino-G-fluoro-ocresol, the total recovery of which amounted to 1376 grams, which corresponds to a per cent y1eld based upon the 4-chloro-2-fluorophenol charged.

Acetic anhydride (800 cc.) and 4-chloro-alphadimethylamino-6-fluoro-o-cresol (345 grams) were refluxed for 16 hours. Fractional distillation of the resulting product through an 18 inch column resulted in the isolation of 360 grams of 5-chloro-3-fiuorosaligenin diacetate, which corresponds to a yield of 82 per cent based upon the 4 chloro-alpha-dimethylamino-S-fluoro-o-cresol used.

5-chloro-3-fluoro-saligenin diacetate was converted to 5-ch1oro-3-fiuoro-saligenin according to the following procedure:

5 chloro 3 fluorosaligenin diaceta'te (260 grams), methanol (1200 cc.) and benzene sulfonic acid (1 gram) were mixed and heated to reflux. A slow distillation through a four foot column (using a reflux ratio of 30:1) was then started. This distillation was discontinued when thetotal distillate (principally the methyl alcohol-methyl acetate azeotrope: boiling point 53 C.) amounted to 900 cc. The residue in the still was then dilutd with water to make a total volume of three liters. A few crystalsof chloro-3-fluorosaligenin were added thereto, and the desired product, which crystallized immediately, was separated from the liquid by filtration and was air dried; Further product was crystallizedbymaking the filtrate slightly alkaline, concentrating it to a volume of 590 c'c., acidifying, and adding a .few crystals of 5chloro-3fluorosaligenin. The total recovery of 5-chloro-3-fluorosaligenin amounted to 175 grams, which corresponds to a 99 per cent yield based upon the 5 chloro-S-fiuorosaligenin diacetate used.

Aqueous sodium hydroxide (400 cc. of one normal caustic), 5-choloro-3 fiuorosaligenin (35.3 grams) and palladium on a charcoal carrier (3 grams of a composition comprising 5 weight per cent of palladium) were placed in a flask and subjected to a hydrogen atmosphere at a total pressure of 30 pounds per square inch gauge. The flask was then placed on a commerical shaker and shaken for about 30 minutes (until a pressure drop of about 15.5 pounds per square inch indicated the reaction of about 0.2 mol of hydrogen). The catalyst was separated from the liquid by filtration, and the filtrate was acidified by hydrochloric acid (50 cc. of a 30 weight per cent solution). The acidified liquid was saturated with sodium chloride; crystals of 3-fluorosaligenin precipitated and were separated by filp,

tration. These crystals were dissolved in acetone (280 cc.), and salt was separated from the acetone solution by filtration. The filtrate was placed in an evaporating dish and the acetone was allowed to evaporate leaving the dry 3- fluoro-saligenin (18 grams). This corresponds to a 64 per cent yield of the desired product.

Aluminum isopropoxide grams), 3-fluorosaligenin (2.84 grams) and tertiary-butyl alcohol (500 cc.) were refluxed for about 16 hours, and volatile material was then distilled to concentrate the solution to 100 cc. Tertiary-butyl alcohol (300 cc.) and o-chlorobenzaldehyde (300 cc.) were added to the concentrate and the resulting mixture was refluxed gently for 16 hours,

8 cooled, and filtered Sulfuric acid (200 cc. 61:2. 10 weight per cent aqueous solution) was added to the cooled mixture, which was then made alkaline by gradual additions ofsodium hydroxide (a 59- weight per cent solution). The alkaline aqueous phase was separated from the organic phase in a separatory funnel, and the organic 7 layer was then extracted twice more with 10 weight per cent aqueous sodium hydroxide (200 cc. portions). The three alkaline extracts were combined, and the resulting solution was steam distilled until no further organic material was detected in the distillate. The residue after this distillation was made acid with acetic acid and p-toluidine (3 grams) in acetic acid (25 cc. of a 20 weight per cent aqueous acid) was added to the acidified solution. The Schiffs base so precipitated, when separated and dried, amounted to 2.15 grams. This indicated a 47 per cent con version of the 3-fluorosaligenin to the correspondirig aldehyde.

We claim: 7

A method of producing 3-fluorosalicylaldehyde that comprises (1) diazotizing 5-chloro-o-anisidine and converting the resulting diazotized.

rnaterial to 4-chloro-2-fluoroanisole by (A) forming the diazonium fiuoborate by the action of fluoboric acid and (B) thermally decomposing the diazonium fiuoborate; (2) hydrolyzingthe l-chloro-Z-fluoroanisole .to produce 4-chloro-2 fluorophen'ol; (3) converting the 4-chloro-2- iluor'ophelnol to 4-ch1oro-6-fluoro-alpha-dimiethylarnino-o-cresol by the action thereon offormaldehyde and dimethylamine; (4) converting the 4-chloroe6-fluoro-alpha-dimethylamino-o-cresol to 5-chloro-3-fiuorosa1igenin diacetate by the action of acetic acid; and (5) refluxing the. 5- chloro-3-fluoi'osaligenin diacetate with methanol in the presence of benzene sulfonic acid to produce 5-chloro-3-fluorosaligenin; (6) dechlorinating. the 5-chloro-3-fluorosaligenin to 3- fiuorosaligenin by. the action of hydrogen inthe presence of 'a palladium catalyst; and ('7) oxidizing the 3-fluorosaligenin to 3-fiuoro-salicylaldehyde by the action of an aromatic aldehyde in the presence of an aluminum alkoxide.

EDGAR C. BRITTON. JAMES D. HEAD.

No references cited. 

